Project Abstract: Dr. Bahr's long-term goal is to become an independent investigator developing novel diagnostic tests for difficult-to-diagnose infectious diseases affecting low-resource populations. Dr. Bahr's research to date has emphasized novel molecular technologies and immunodiagnostics to detect TB meningitis. This K23 award will provide the mentored clinical research experience, didactics, and training in biostatistics, immunology, study design, regulation, and novel diagnostic test development required for him to establish himself as an independent researcher. Research: Rapid, accurate diagnostic tests are urgently needed for a myriad of infectious diseases that affect low-income populations and carry high mortality rates. Approximately 1% of TB cases worldwide develop meningitis. TB meningitis has an unacceptably high mortality rate (>50%), in large part due to slow and insensitive diagnostics. Dr. Bahr's work with GeneXpert MTB/Rif and the re-engineered GeneXpert MTB/Rif Ultra has provided evidence to support the use of new, rapid (~2hrs) molecular diagnostic tools with improved accuracy. Yet, up to one third of TB meningitis cases are missed, even with these improved tests. Adjunctive, novel, immunologic diagnostics may provide improved diagnostic accuracy for TB meningitis. Histoplasmosis is common throughout much of the United States and Latin America. In the United States, diagnosis is made by antigen detection; however, this approach is inadequate and is unavailable in much of the world where only culture and/or histopathology are available. Diagnosis is particularly difficult for sub-acute/chronic pulmonary histoplasmosis. The development of an interferon gamma release assay (IGRA) directed at Histoplasma capsulatum may improve diagnosis of pulmonary histoplasmosis, leading to improved outcomes. In both conditions, inadequate diagnostic tests based on pathogen detection lead to delayed diagnosis, reliance on empiric therapy, and poor outcomes. Alternative diagnostic approaches focused on the host immune response may provide better results. The aims of this proposal are: 1) To determine if GeneXpert MTB/Rif Ultra can improve TB meningitis diagnosis in comparison to Xpert MTB/Rif, culture, and post-mortem testing, 2) To determine if novel immunologic biomarkers, when added to standard microbiologic/molecular techniques, can improve TB meningitis diagnosis, in comparison to conventional techniques alone, and 3) To determine if a novel Histoplasma capsulatum IGRA can improve diagnosis of pulmonary histoplasmosis, compared to antigen detection, culture, and histopathology. Together, these aims have the potential to significantly improve the diagnosis of TB meningitis and pulmonary histoplasmosis. The findings from these proposed studies and the proposed training in biostatistics, immunology, study design and regulation, and diagnostic test development will inform an R01 proposal to further evaluate novel diagnostic tests for infectious diseases.